Throughout this application various publications are referred to by partial citations within parenthesis. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications, in their entireties, are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Transporters throughout the body control the solute composition of the CSF, urine, plasma, and other extracellular fluids. In the brain, neurotransmitter transporters serve specialized functions related to the modulation of synaptic transmission. The recent cloning of genes encoding neurotransmitter transporters is facilitating the elucidation of the role of transport proteins in nervous system health and disease. The availability of cloned transporters provides the opportunity to define the pharmacological profiles of specific gene products, map their patterns of distribution, and make correlations with in vivo observations to better understand their biological functions.
Since the description of the primary structure of the first neurotransmitter transporter (the GABA transporter GAT-1; Guastella et al., 1990) at least 10 additional transporters with related sequences have been cloned (see Amara and Kuhar, 1993 for review), defining a new gene family. Members of this family typically exhibit from .about.40% to .about.70% overall amino acid identity with each other, and share a number of structural and functional features, including 12 predicted transmembrane domains, potential sites for glycosylation in extracellular domains, and dependence on sodium for transport activity. Transporters in this family include those for norepinephrine (Pacholczyk et al., 1991), serotonin (Blakely et al., 1991; Hoffman et al., 1991), dopamine (Kilty et al., 1991; Shimada et al., 1991), glycine (Smith et al., 1992a; Guastella et al., 1992; Liu et al., 1992b; Borowsky et al., 1993), GABA (Guastella et al., 1990; Clark et al., 1992; Borden et al., 1992; Liu et al., 1993), betaine (Yamauchi et al., Lopez-Corcuera et al., 1992), taurine/.beta.-alanine (Uchida et al., 1992; Smith et al., 1992; Liu et al., 1992), L-proline (Fremeau et al., 1992), and creatine (Guimbal and Kilimann, 1993). Each of these transporters has been found in the brain and nearly all have substrates that are either neuroregulators, osmoregulators, or both, reinforcing the concept that molecules with similar structures often have similar functions.
In addition to those described above, several transporters have been cloned that exhibit significant amino acid identity with the neurotransmitter transporters, but whose endogenous substrates have not yet been identified (Uhl et al., 1992; Liu et al., 1993a). We describe here the cloning and localization of a novel "orphan" transporter from rat brain, rB21a, whose structural homology with neurotransmitter transporters indicates it is a member of this gene family. Its presence in the brain further suggests that its endogenous substrate may be neuroactive; in fact, it has been suggested that identifying the substrates of "orphan" transporters could reveal previously undescribed neurotransmitter systems (Uhl, 1992). The cloning of rB21a provides the means to determine its functions in the nervous system. As a novel transporter homologous to neurotransmitter transporters, rB21a may be useful as a target for the development of therapeutic agents for neurological and psychiatric disorders.